Field of the Invention
The present invention relates to reducing or inhibiting cardiac dysfunction due to heart failure by administering at least one bisphosphonate compound, and more specifically, wherein the bisphosphonate compound increases expression and/or phosphorylation of at least one kinase having biological activity in heart tissue.
Related Art in the Field
The prevalence of heart failure (“HF”) has grown to epidemic proportions as the population ages. HF may be caused by many forms of heart disease. Common causes of heart failure include: narrowing of the arteries supplying blood to the heart muscle (coronary heart disease); prior heart attack (myocardial infarction) resulting in scar tissue large enough to interfere with normal function of the heart; high blood pressure; heart valve disease due to past rheumatic fever or an abnormality present at birth; primary disease of the heart muscle itself (cardiomyopathy); and infection of the heart valves and/or muscle itself (endocarditis and/or myocarditis). Each of these disease processes can lead to heart failure by reducing the strength of the heart muscle contraction, by limiting the ability of the heart's pumping chambers to fill with blood due to mechanical problems or impaired diastolic relaxation, or by filling the heart's chambers with too much blood.
Cardiovascular disease is the leading cause of death in the Western world, resulting in an estimated annual death toll of more than ten million people. Such diseases, such as chronic hypertension (high blood pressure), left ventricular hypertrophy (enlargement of the heart), and myocardial ischemia (cardiac cell injury) can culminate in heart failure.
One consequence of hypertension is generally hypertrophy. Cardiac hypertrophy is an increase in the size of the heart. In humans, hypertrophy, is the compensatory response of the myocardium (cardiac muscle) to increased work as a result of an increase in blood pressure or blood volume (hemodynamic overload). Hypertrophy of the myocardium may become increasingly harmful due to the increased metabolic requirements of the enlarged heart. Moreover, ischemic heart disease and cardiac arrhythmias may develop, increasing the risk of death. Cardiac arrhythmias may arise from abnormalities in impulse formation, impulse conduction, or a combination of both. The regulation of impulse formation and conduction involves a complex interaction between the autonomic nervous system, cardiac ion channels, and cardiac gap junctions.
Gap junctions are specialized regions of the cell membrane that directly connect the cytoplasmic compartment of two neighboring cells. In cardiomyocytes, gap junctions cluster at the intercalated disc, a unique microdomain located at the ends of adjoining cardiomyocytes that help coordinate the ordered depolarization of adjacent cardiomyocytes. The gap junction channels are composed of two hemichannels (connexons) provided by each of two neighboring cells. Each connexon consists of six proteins called connexins. The distribution of the different types of connexins (Cx) varies throughout the heart. The gap junction channel can switch between an open and a closed state by a twisting motion. The conduction of the electrical impulse takes place through the gap junctions and normally functioning gap junctions are therefore a prerequisite for normal conduction and thereby normal rhythm of the heart. Disruption of gap junction organization is a common, and highly arrhythmogenic feature, of both acquired and inherited myopathies. Moreover, dynamic remodeling of gap junctions occurs during ischemia, promoting potentially fatal arrhythmias.
Heretofore, the development of antiarrhythmic drugs has focused primarily on either the autonomic nervous system or ion channels, with little attention to pharmaceuticals that may alter gap junction stability. Further, the currently available drugs are not without negative side effects. Specifically, the negative effects fall into two general categories: the usual kinds of side effects seen with many drugs (such as allergies, insomnia, gastrointestinal disturbances, etc.), and proarrhythmia. It is proarrhythmia that poses the major problem with antiarrhythmic drugs because ion channel modulators often suppress one arrhythmia while promoting another. Proarrhythmia simply means causing cardiac arrhythmias, and as such, instead of eliminating arrhythmias these drugs can actually produce them.
Therefore, there is an immediate need for therapeutic agents that prevent and/or reverse the damage caused by myocardial dysfunction without harming healthy cells. Due to the serious side effects that limit the use of the present drugs a new class of drugs with a completely different mode of action is desirable.